An integrative genomic and chemical similarity approach linking fungal secondary metabolites and biosynthetic gene clusters

Abstract

Fungi are well known to biosynthesize structurally complex secondary metabolites (SMs) with diverse bioactivities. These fungal SMs are frequently produced by biosynthetic gene clusters (BGCs). Linking SMs to their BGCs is key to understanding their chemical and biological functions. Reasoning that structural similarity of SMs arises from similarities in the genes involved in their biosynthesis, we developed an integrative approach that leverages known BGC-SM pairs to predict global links across SMs and BGCs in fungi. As proof of concept, we systematically interrogated metabolomes and genomes of 16 strains of the filamentous fungus Aspergillus fischeri, detecting a total of 60 metabolites. Of those, we were able to assign 22 to known BGC-SM pairs and propose specific hypotheses for the remaining 38 metabolites. These results suggest that coupling genomic similarity and chemical structure-based similarity is a straightforward and high-throughput approach for linking fungal SMs to their BGCs.